Dos Passos wrote 42 novels, as well as poems, essays, and plays. His politics undergird all his writing; he was a leading participant in the 1936 First Americans Writers Congress and in the 1930s served on the American Committee for the Defense of Leon Trotsky. He later moved from socialism to libertarianism, and in the 1960s he campaigned for presidential candidates Barry Goldwater and Richard Nixon. His influence on other writers was substantial, especially in his use of nonlinear fiction, and his trilogy, U.S.A. (1938) has been hailed as "The Great American Novel."

His novels include Three Soldiers (1920), Manhattan Transfer (1925), Orient Express (1927), the trilogy District of Columbia (1952), and Mr. Wilson's War (1962). He also wrote a memoir, The Best of Times (1966) and a book of poems, A Pushcart at the Curb (1922). He lived in this house as a child.